Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents with novel structural skeleton

Article abstract of DOI:10.1016/j.bmcl.2018.06.016

A series of new azoalkyl ether imidazo[2,1-b]benzothiazoles were developed via a convenient synthetic procedure. The antimicrobial assays showed that a good number of the prepared derivatives exhibited significant inhibitory properties against most of the

Full text of DOI:10.1016/j.bmcl.2018.06.016

Accepted Manuscript
Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial
agents with novel structural skeleton
Swetha Kameswari Maddili, Zhen-Zhen Li, Vijaya Kumar Kannekanti,
Rammohan R. Yadav Bheemanaboina, Balaraju Tuniki, Vijai Kumar Reddy
Tangadanchu, Cheng-He Zhou
PII:
S0960-894X(18)30504-3
https://doi.org/10.1016/j.bmcl.2018.06.016
BMCL 25897
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 April 2018
8 June 2018
10 June 2018
Please cite this article as: Maddili, S.K., Li, Z-Z., Kannekanti, V.K., Yadav Bheemanaboina, R.R., Tuniki, B.,
Tangadanchu, V.K.R., Zhou, C-H., Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents
with novel structural skeleton, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/
j.bmcl.2018.06.016
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Bioorganic & Medicinal Chemistry Letters
jour nal homepage: w ww.elsevier. com
Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents
with novel structural skeleton
Swetha Kameswari Maddili, Zhen-Zhen Li, Vijaya Kumar Kannekantia, Rammohan R. Yadav
Bheemanaboinab, Balaraju Tunikic, Vijai Kumar Reddy Tangadanchua, Cheng-He Zhou*
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of new azoalkyl ether imidazo[2,1-b]benzothiazoles were developed via a convenient
synthetic procedure. The antimicrobial assays showed that a good number of the prepared
derivatives exhibited significant inhibitory properties against most of the tested strains.
Especially 2-methyl-5-nitroimidazole derivative 5a presented superior inhibit activity against
MRSA and B. typhi with MIC = 4 µg/mL and MIC =1 µg/mL, respectively. The highly active
compound 5a showed low toxicity against mammalian cells without obvious triggering of the
development of bacterial resistance, and it also possessed rapid bactericidal efficacy.
Molecular docking study exposed that the active molecule 5a could interact with the active site
of S. aureus gyrase through hydrogen bond. Quantum chemical studies were also performed to
explain the high antibacterial activity. Further investigation revealed that compound 5a could
significantly associate with gyrase−DNA complex by mean of hydrogen bonds and could
efficiently intercalate into MRSA DNA to form 5a−DNA supramolecular complex, which
impart potent bioactivity.
Revised
Accepted
Available online
Keywords:
Imidazo[2,1-b]benzothiazole
Antimicrobial
Antifungal
MRSA DNA interaction
Molecular modeling
2017 Elsevier Ltd. All rights reserved.
Infectious diseases instigated by the invasion of the
pathogenic microorganisms continue to be a major health threat
due to increased resistance to the existing antimicrobial drugs,
even with substantial progress in the antimicrobial treatment.1,2
The prevalence of bacterial resistance to various antibacterial
agents such as sulfonamides, glycopeptides, nitroimidazoles, β-
lactams, quinolones, chloramphenicols, macrolides, and
tetracyclins are of foremost concern. Methicillin Resistant
Staphylococcus aureus (MRSA) is one of the most nosocomial
pathogens with the properties of antibiotic resistance in the recent
times. MRSA could be any strain of Staphylococcus aureus that
has acquired multiple drug resistance to β-lactam class of
antibiotics by means of horizontal gene transfer and natural
selection.3 In addition, MRSA has the characteristic ability to
sustain penicillin-like antibiotics which usually inhibit bacterial
growth by impeding cell wall synthesis. However, this is brought
about by mecA, a resistance gene, which obstructs β-lactam
antibiotics from disabling the crucial enzymes for cell wall
synthesis like transpeptidases.4 Accordingly, the infections
caused by MRSA associated with excessive morbidity and
mortality are now treated as a global challenge.5 As a
consequence of these facts, the research on novel drugs bearing
high competence for these pathogens and less toxicity to the host
which may be different from existing resistant drugs is of
considerable exploration.3
Benzothiazole is an aromatic heterocyclic system having
various biological activities such as antimicrobial, anticancer,
anticonvulsant, anti-inflammatory, anti-alzheimer, anti-psychotic,
antidiabetic, diuretic and protein tyrosine inhibitor activities.6
Additionally, imidazo[2,1-b]benzothiazole derivatives are fused
tricyclic sulfur and nitrogen-containing heterocycles, frequently
encountered in pharmaceutical chemistry as bioactive molecules
and reported to be associated with promising biological activities
such as antitumor, antimicrobial, antibacterial and antiallergic
agents.7–9 Also, imidazo[2,1-b]benzothiazoles demonstrated a
large extent of pharmacological properties like antimicrobial
activity and potentiality to combat drug resistance. 10–12
Azoles such as imidazoles and triazoles are a significant class
of nitrogen heterocycles with multiple heteroatoms, aromaticity
and electron rich properties. 13–14 The exceptional structure makes
azole-based derivatives not only bind effortlessly through
noncovalent interactions like coordination and hydrogen bonds
with enzymes and receptors in living organisms, but also affect
the binding affinity and water solubility of conjugated system,
thus allow azoles imparting diverse applications in the scope of
medicinal chemistry.15 Thereby this privileged class exert wide
———
* Corresponding author. Tel./fax: +86-23-68254967.
E-mail: zhouch@swu.edu.cn (C.-H. Zhou)
a Postdoctoral fellows from CSIR-Indian Institute of Chemical Technology
(IICT), India.
b Postdoctoral fellow from CSIR-Indian Institute of Integrative Medicine
(IIIM), India.
pharmacological
antitubercular,
profile like antibacterial, antifungal,
anticancer, antiviral, antiproliferative,
c Department of Chemistry, GITAM University, Hyderabad 502 329, India.

antihistaminic, anticonvulsant, antihypertensive and other
properties. 16 Consequently we intended to design novel potential
drugs with enhanced antimicrobial efficacy by combining two
active pharmacophores via a linker bridge.
in vitro against four Gram-positive bacteria, six Gram-negative
bacteria and five fungi. The preliminary antimicrobial
mechanism was investigated by evaluating the interactions of the
prepared highly active compounds with calf thymus DNA.
Bactericidal kinetic assay and resistance developing ability were
also investigated. Moreover, the molecular modeling and
experimental investigation of the highly active compound with
DNA were further studied to explore the possible antibacterial
mechanism.
The intended azoalkyl ether imidazo[2,1-b]benzothiazole
derivatives 5–7 were prepared by involving multiple step
reactions starting from commercially available benzothiazol-2-
amine and/or 6-ethoxybenzothiazol-2-amine as represented in
Scheme 1. Condensation of benzothiazol-2-amine and/or 6-
ethoxybenzothiazol-2-amine and phenacyl bromide in the
o
presence of ethanol at 70 C produced compounds 2a–b in 90–
92% yield, which was then subjected to hydroxyl methylation
using acetic acid and sodium acetate at 60 oC to afford
compounds 3a–b with 74–76 %.20 The prepared intermediates
3a–b were treated with different alkyl dibromides and sodium
hydride in THF at room temperature for several hours to achieve
the desired compounds 4a–f in yields of 84–89%. Finally, the
target imidazo[2,1-b]benzothiazole azoles 5a–f, 6a–f and 7a–f
were conveniently and efficiently obtained in 80–94% yields by
the reaction of O-alkyl bromides 4a–f with 2-methyl-5-
nitroimidazole, 4-nitroimidazole, 1,2,4-triazole in acetonitrile at
Figure 1. Design of novel target hybrids of azoalkyl ether imidazo[2,1-
b]benzothiazoles.
o
50 C in the presence of potassium carbonate, respectively. All
1
the prepared compounds were characterized by H NMR, 13C
Aiming to better understand the structure–activity relationship
and increace flexibilities, various lengths of alkyl chains were
introduced. Researches provide evidence that aliphatic ether
linker could improve lipid solubility, meanwhile different alkyl
linkers have the ability to modulate lipid solubility and
physicochemical properties.17-19 The antibacterial and antifungal
potencies of all the newly synthesized compounds were evaluated
NMR, IR and HRMS spectra. However, the compound purity
was estimated through the aid of quantitative nuclear magnetic
resonance (QNMR) technique with 1,3,5-trioxane as internal
standard. All the synthesized compounds were uncovered to be
more than 95% pure and the spectral information was listed in
the Supporting Information.
Scheme 1. Synthetic routes of target azoalkyl ether imidazo[2,1-b]benzothiazoles. Reagents and conditions: i) Phenacyl bromide, C2H5OH, 70 oC; ii) CH3COOH,
CH3COONa, 50 oC; iii) Alkyl dibromides, NaH, THF, rt, 6 h: iv) 2-Methyl-5-nitroimidazole, K2CO3, CH3CN, 50 oC, 5 h; v) 4-Nitroimidazole, K2CO3, CH3CN,
50 oC, 5 h; vi) Triazole, K2CO3, Acetonitrile, 50 oC, 5 h.
Two-fold serial dilution technique was used to investigate the
antimicrobial activity as recommended by the Clinical and
Laboratory Standards Institute (CLSI).21 The results are shown in
Table 1. It is revealed that a good number of the tested

compounds could significantly obstruct the growth of tested
bacterial strains. Excitingly, compounds 4a, 5a–b and 6b could
successfully inhibit the growth of MRSA at the concentrations of
4–8 µg/mL, which were more effective than chloromycin (MIC =
16 µg/mL). Especially, 2-methyl-5-nitroimidazole derivative 5a
with propyl linker to imidazo[2,1-b]benzothiazole backbone gave
stronger antibacterial efficacy and broader bioactive spectrum
than norfloxacin and chloromycin with quite low MIC values. It
was 4 to 8-fold more active against MRSA (MIC = 2 µg/mL)
than both the standard drugs norfloxacin and chloromycin
correspondingly. It was particularly observed that the MIC values
of compounds 5a and intermediate 4a were posing 4-fold better
activity profile against S. dysenterie than those of norfloxacin
(MIC = 16 µg/mL) and chloromycin (MIC = 16 µg/mL),
respectively. Most of the prepared compounds exhibited
comparable activity (MIC = 2–32 µg/mL) against B. subtilis to
standard drugs norfloxacin (4 µg/mL) and chloromycin (MIC =
32 µg/mL). The results also evidenced that intermediates 4d–f
apart from 4a–c presented weak or no apparent activities in
restraining the growth of tested microorganisms.
and B. yeast, which exerted comparable or superior inhibitory
potency to the first-line antifungal drug fluconazole. Almost all
the synthesized compounds with electron donating –OCH2CH3
group at the 6-position gave weak influence in antifungal
activities. On the contrary, compound 4a with smallest alkyl
chain could efficiently inhibit the growth of A. flavus in vitro
with MIC values of 4 µg/mL, which was 64-fold more
intoxicating than Fluconazole (MIC = 256 µg/mL). Surprisingly,
the 2-methyl-5-nitroimidazole derivative 5a displayed not only
good antibacterial activities against all the tested bacterial strains,
but also revealed excellent antifungal activities against A. flavus,
C. mycoderma and C. albicans in low inhibitory concentrations
(MIC = 4–16 µg/mL).
We extended our further focus to study the effect of alkyl
chain as a large amount of literatures has disclosed the role of
alkyl chain length in affecting antimicrobial potency.22 Different
lengths of alkyl chains varied the impact over the biological
efficacy in which derivatives 4−7a with propyl chain gave better
antibacterial properties in comparison with other alkyl
derivatives. However, the derivatives 4−7f with decyl extended
groups presented weak or no obvious activity in hindering the
growth of the tested strains. These experimental findings
manifested that only the appropriate length of alkyl chain as a
linker was obligatory for exerting significant antimicrobial
efficacy. Both the antibacterial as well as antifungal activity
results were also briefly discussed in the Supporting Information.
The in vitro antifungal assay results in Table S1 manifested
that the antifungal activity of the synthesized derivatives had
similar inhibitory potency as their antibacterial efficacy, though
relatively weaker than the latter. Imidazo[2,1-b]benzothiazole
derivatives lacking ethoxy group at 6-position 5a–b, 6a-b and
7a-b demonstrated good inhibitory efficacy against all the tested
fungal strains with MIC values of 2–64 µg/mL excluding C. utilis
Table 1 MIC values (ug/mL) of compounds 4–7.a, b, c
Gram-positive bacteria
Gram-negative bacteria
Compds
S.
aureus
B.
subtilis
M.
luteus
E. coli
(DH52)
E. coli
JM109
S.
dysenterie
P.
aeruginosa
B.
proteus
B.
typhi
MRSA
4a
4b
4c
8
16
64
32
32
32
4
4
8
32
256
32
16
16
16
32
16
4
16
64
8
16
16
16
16
16
16
128
128
8
128
>512
>512
>512
4
4d
16
>512
>512
>512
2
>512
>512
>512
8
>512
128
>512
4
>512
>512
>512
32
>512
128
>512
4
>512
128
>512
4
>512
128
>512
8
4e
>512
16
>512
256
1
4f
5a
2
5b
5c
8
16
4
16
16
16
64
8
16
2
16
32
8
16
16
16
32
64
256
128
256
512
256
256
128
256
512
512
64
8
32
5d
5e
16
32
16
16
8
32
32
8
>512
128
8
8
16
128
128
4
32
32
512
32
512
256
4
128
16
>512
512
8
128
64
>512
16
512
128
2
512
64
>512
256
4
64
32
256
256
32
128
64
5f
6a
6b
6c
2
128
64
8
128
16
6d
6e
512
>512
32
128
128
128
4
16
32
256
256
32
512
128
64
256
>512
512
16
16
64
256
16
512
512
32
512
512
256
16
256
256
32
6f
7a
7b
7c
8
16
8
16
16
16
8
32
16
32
4
32
32
32
256
64
32
16
16
32
32
128
>512
>512
64
16
7d
7e
256
128
64
>512
>512
128
32
>512
>512
64
>512
>512
8
>512
>512
32
>512
>512
64
>512
>512
32
>512
256
64
>512
>512
8
7f
Chloromycin
Norfloxacin
16
8
16
2
32
4
8
2
32
1
32
1
16
16
32
16
32
8
4
a Minimum inhibitory concentrations were determined by micro broth dilution method for microdilution plates.
b
MRSA, Methicillin-Resistant Staphylococcus aureus (N315); S. aureus, Staphylococcus aureus ATCC25923; B. subtilis, Bacillus subtilis; M. luteus,
Micrococcus luteus ATCC4698; E. coli DH52, Escherichia coli DH52; E. coli JM109, Escherichia coli JM109; S. dysenteriae, Shigella dysenteriae; P.
aeruginosa, Pseudomonas aeruginosa; B. proteus, Bacillus proteus ATCC13315; B. typhi, Bacillus typhi.
Majority of the clinically consented antimicrobial drugs have
tolerated overthrow from the resistant microbial strains because
of their escalated sensitivity or reduced potency to the
degradation process.23 In this manner, the assessment of the
ability of derivative 5a to control the resistance development is of
immense consideration. MRSA is one of the most resistant
strains which was taken as the tested form while chloromycin
was considered as positive control. As displayed in Figure 2, this

outcome manifested that MRSA experienced more difficulty to
develop resistance against compound 5a when compared to the
clinical drug, and thus this structure through substantial
therapeutic potency and low drug-resistance might serve as a
hopeful anti-MRSA candidate.24
The molecular electrostatic potential (MEP) surface gives an
indication of the charged surface area, a concept for explaining
the hydrophilicity of compounds and the orientation of drug
candidates for their activities.26 Thus, the MEPs were performed
to examine the similarities and differences in electrostatic
binding characteristic of the surface of molecules (Table 3). The
comparison of the electrostatic maps of hybrids 5a, 5d, 6a, 7a
and 7h revealed that molecule 5a possessed more negative
charged regions (in red) on the nitro group of 2-methyl-5-
nitroimidazole and nitrogen atoms of imidazo[2,1-
b]benzothiazole. It might indicate the capability of forming
hydrogen bond with share of nitro group and nitrogen atoms of
imidazo[2,1-b]benzothiazole ring. This was consistent with the
binding mode from docking study.
250
Chloromycin
Compound 5a
200
150
100
50
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15
Passages
Figure 2. Evaluation of resistance development against compound 5a in
bacterial strain MRSA.
With the intention to comprehend the antibacterial property of
compound 5a, time–kill kinetic experiment was performed
against MRSA, which would deliver further details regarding the
bactericidal potency of molecule 5a against the tested MRSA
strain. As shown in Figure 3, compound 5a could instigate more
than 3-Log (CFU/mL) decline in the count of viable bacteria
within an hour at a concentration of 4 × MIC. Therefore, this 2-
methyl-5-nitroimidazole derivative 5a was estimated to initiate
instant bactericidal efficacy against tested MRSA.
Figure 4. The binding mode of compound 5a overlap with cocrystal ligand
12
Compound 5a
Control
10
8
6
4
2
Figure 5. The binding mode of compound 5a and S. aureus gyrase DNA
supramolecular complex.
120
150
180
210
240
Time (min)
Deoxyribonucleic acid (DNA) carries the genetic information
required for the growth and metabolism of the living organisms
as well as acts as a significant molecular target for investigating
smaller drug molecules bearing biological properties. The
investigation about drug–DNA interaction is of immense
consideration in the interest in coherent design and fabrication of
novel and efficient DNA–targeting agents.27 UV-vis
spectroscopic methods were used to study about the nature of
binding between the extremely active compound 5a and MRSA
DNA at the molecular level. These results disclosed that
compound 5a could meritoriously intercalate into MRSA DNA
by forming 5a–DNA complex, which might further hinder the
DNA replication process consequently exhibiting momentous
antimicrobial potency (Supporting Information). As in Figure S1,
the absorption maximum wavelength of DNA was first observed
at 260 nm which showed gradual increase associated by a slight
hypsochromic shift with the raising concentration of compound
5a. Moreover, the absorption wavelength of 5a–DNA complex
(inset of Figure S1) was recorded somewhat lesser than that of
the sum of free DNA and free compound 5a which signified that
Figure 3. Representative time-kill studies of compound 5a at 4 × MIC against
MRSA.
Molecular docking study was conducted to vindicate the
detected antibacterial inhibition and thus investigate the possible
antibacterial action mechanism of compounds.25 As shown in
Figures 4 and 5, hybrid 5a was able to dock into the active site of
S. aureus gyrase DNA (PDB code: 2XCS) with the lowest
binding energy of −9.338 kcal mol−1. Molecule 5a could form
with gyrase−DNA complex by means of π-π stacking between
the two carbonyl groups of the imidazo[2,1-b]benzothiazole
backbone and base pairs of DNA (DG-11 and DG-10). The
nitrogen atom of the azole ring presented hydrogen bonding with
the residue MET-1121. Additionally, the nitro group showed
closely interaction with residue AGP-1083, which signified the
role of nitro group in exerting strong bioactivity. These
supporting interactions might be beneficial to stabilize the 5a-
enzyme-DNA supramolecular complex, which might be
accountable for the potent inhibitory activity of compound 5a
against the drug resistant MRSA.

a weak hypochromic effect has occurred between the MRSA
DNA and compound 5a. Consequently, both the hypsochromic
effect and hyporchromic region preliminarily disclosed that the
interaction mode of compound 5a was via intercalation into DNA.
Furthermore, the intercalation of the compound 5a chromophore
into the DNA double helix and the dense overlap of π-π*
electronic levels in the large π-conjugated system with that of
DNA base electronic states were in accordance with the
displayed spectral changes.
to have broad antibacterial spectrum against most of the tested
bacterial and fungal strains in contrast to reference drugs
chloromycin, norfloxacin and fluconazole. In particular, it could
significantly obstruct the multiplication of MRSA and B. typhi
with MIC of 2 µg/mL and 1 µg/mL, respectively. Furthermore,
compound 5a could instantly exterminate MRSA and did not
apparently
stimulate bacterial
resistance.
Preliminary
experimental findings disclosed revealed that compound 5a could
associate with DNA-gyrase by means of hydrogen bonds and
form a stable 5a–DNA complex with MRSA DNA through
intercalation mode, thus imparting efficient biological potency.
Quantum chemical studies were also performed to understand the
structural features essential for bioactivity. Henceforth,
compound 5a might serve as a significant multi-targeting anti-
MRSA agent and deserve further exploration.
Table 2 Comparison of the MEP surfaces of compounds 5a, 5d, 6a and 7a.
Compds
MEPs
Acknowledgments
This work was partially supported by National Natural
Science Foundation of China (No. 21672173), the Research Fund
for International Young Scientists from International (Regional)
Cooperation and Exchange Program of NSFC (No.
81450110094), China Postdoctoral Science Foundation
(2018M633313), Chongqing Special Foundation for Postdoctoral
Research Proposal (No. Xm2017184), and Program for Overseas
Young Talents from State Administration of Foreign Experts
Affairs, China (Nos. WQ2017XNDX047, WQ20180083).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/
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Azoalkyl ether imidazo[2,1-
b]benzothiazoles as
potentially antimicrobial
agents with novel structural
skeleton

1. Novel azoalkyl ether imidazo[2,1-b]benzothiazole
analogues were prepared.
2. Compounds 5a is active against MRSA stains than
Chloromycin and Norfloxacin.
3. Highly active compound 5a show DNA
interaction via intercalation mode.
4. MRSA showed no developed resistance towards
Compound 5a.